PERIOPERATIVE MEDICINE Xenon and Isoflurane Reduce Left Ventricular Remodeling after Myocardial Infarction in the Rat Anna B. Roehl, M.D.,* Sandra Funcke, M.D.,† Michael M. Becker, M.D.,‡ Andreas Goetzenich, M.D.,§ Christian Bleilevens, M.Sc.,|| Rolf Rossaint, M.D.,# Paul Steendijk, M.D., Ph.D.,** Marc Hein, M.D.* ABSTRACT What We Already Know about This Topic • Previous studies have demonstrated that xenon and isoflu- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1385/260290/20130600_0-00026.pdf by guest on 24 September 2021 Background: Xenon and isoflurane are known to have car- rane have cardioprotective properties. • However, little is known about the long-term effects of xenon dioprotective properties. We tested the hypothesis that these and isoflurane on cardiac remodeling after perioperative myo- anesthetics positively influence myocardial remodeling 28 cardial infarction. This study determined the long-term effects days after experimental perioperative myocardial infarction of anesthetic preconditioning on cardiac remodeling after perioperative myocardial infarction using a rat model of left and compared their effects. ventricular ischemia-reperfusion injury. Methods: A total of 60 male Sprague–Dawley rats were sub- jected to 60 min of coronary artery occlusion and 120 min of reperfusion. Prior to ischemia, the animals were random- ized for the different narcotic regimes (0.6 vol% isoflurane, What This Article Tells Us That Is New 70 vol% xenon, or intraperitoneal injection of s-ketamine). • Compared to isoflurane, xenon limited adverse cardiac re- Acute injury was quantified by echocardiography and tro- modeling and contractile dysfunction after perioperative myo- cardial infarction. ponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compro- mise. Cardiac remodeling was characterized by quantifica- after 4 weeks. Xenon in contrast to isoflurane or ketamine tion of dilatation, hypertrophy, fibrosis, capillary density, anesthetized animals demonstrated a lower remodeling apoptosis, and expression of fetal genes (α/β myosin heavy index (0.7 ± 0.1 vs. 0.9 ± 0.3 and 1.0 ± 0.3 g/ml), better ejec- chains, α-skeletal actin, periostin, and sarco/endoplasmic reticu- tion fraction (62 ± 9 vs. 49 ± 7 and 35 ± 6%), and reduced Deepa Koshi lum Ca2+-ATPase). expression of β-myosin heavy chain and periostin. The effects Results: Whereas xenon and isoflurane impeded the acute on hypertrophy, fibrosis, capillary density, and apoptosis Xenon and Cardiac Remodeling effects of ischemia-reperfusion on hemodynamics and myo- were comparable. cardial injury at a comparable level, differences were found Conclusions: Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and ROEHL ET AL. contractile dysfunction 28 days after perioperative myocar- dial infarction. * Anesthetist, Department of Anesthesiology, University Hos- June pital Aachen, Aachen, Germany. † Resident, Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, ERIOPERATIVE myocardial infarction is a serious Hamburg, Germany. ‡ Cardiologist, Department of Cardiology, P adverse event during surgery and is associated with University Hospital Aachen. § Anesthetist, Department of Cardiac 1 2013 Surgery, University Hospital Aachen. || Research Assistant, Depart- high complication and mortality rates. Left ventricular ment of Anesthesiology, University Hospital Aachen. # Profes- remodeling following myocardial infarction leads to sor, Department of Anesthesiology, University Hospital Aachen. progressive hypertrophy, chamber dilatation, and ultimately 2013 ** Associate Professor, Department of Cardiothoracic Surgery, β Leiden University Medical Center, Leiden, The Netherlands. heart failure. Treatments that block the -adrenergic and Received from the Department of Anesthesiology, University renin–angiotensin–aldosterone system, as well as mechanical 2,3 Anesthesiology Hospital of Aken, Aachen, Germany. Submitted for publication July support, can limit or reverse this process. The extent of 20, 2012. Accepted for publication December 20, 2012. This study the remodeling process is highly dependent on the initial was supported by the German Research Foundation (Bonn, Ger- many; Fund No. Ro 2000/10–1) and Air Liquide Medical GmbH infarct size and thus could be limited by myocardial salvage 118 4 (Düsseldorf, Germany). This study was presented at the “25. Wis- achieved by reperfusion therapy. As shown in short-term senschaftliche Arbeitstage der DGAI,” Würzburg, Germany, on studies, anesthetic preconditioning not only reduces initial 6 February 11, 2011. myocardial injury,5,6 but also prevents activation of the Address correspondence to Dr. Hein: Department of Anes- 7 thesiology, University Hospital of Aken, Pauwelsstrasse 30, 52074 deleterious gene expression profile. However, long-term 1385 Aachen, Germany. [email protected]. Information on purchasing effects of anesthetic preconditioning on cardiac remodeling reprints may be found at www.anesthesiology.org or on the mast- with respect to long-term function after transient ischemia head page at the beginning of this issue. ANESTHESIOLOGY’S articles are made freely accessible to all readers, for personal use only, 6 have yet to be identified. Therefore, we used a rat model of left 94 months from the cover date of the issue. ventricular ischemia-reperfusion (IR) injury to examine the Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott effects of isoflurane and xenon anesthesia on cardiac function, Williams & Wilkins. Anesthesiology 2013; 118:1385-94 structure, and expression of fetal genes after 4 weeks. Anesthesiology, V 118 • No 6 1385 June 2013 <zdoi;10.1097/ALN.0b013e31828744c0> Xenon and Cardiac Remodeling Materials and Methods ropivacaine (Astra Zeneca, Wedel, Germany). Metamizole Animals (Ratiopharm, Ulm, Germany) was injected intraperitoneally A total of 60 male Sprague–Dawley rats (10–12 weeks old, (20 mg/kg) and added to the tap water (10 mg/ml/kg) for 3 350–420 g) were purchased from Charles River Laborato- days. The rats were transferred to a warm isolation chamber ries (Charles River, Sulzfeld, Germany). All of the experi- (Vetario S10 Intensive Care Unit, Brinsea, Sandford, United ments were performed in accordance with the German Kingdom) for recovery. legislation governing animal studies, followed The Principles of Laboratory Animal Care (National Institute of Health, Instrumentation on Day 28 publication No. 85-23, revised in 1996), and had prior Anesthesia was induced with a reduced intraperitoneal approval by the governmental animal care and use office dosage of s-ketamine (120 mg/kg). A three-lead electro- (Landesamt für Natur, Umwelt und Verbraucherschutz Nor- cardiogram was obtained and a third echocardiographic Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1385/260290/20130600_0-00026.pdf by guest on 24 September 2021 drhein-Westfalen, Recklinghausen, Germany, Protocol No. examination performed. The animals were intubated and 9.93.2.10.35.07.210). ventilated as on the first day. The right jugular vein was cath- eterized, and a 2F conductance catheter (SPR-869, Millar Instrumentation and Protocol on Day 0 Instruments, Houston, TX) was inserted via the right carotid After induction of anesthesia by an intraperitoneal injection artery into the left ventricle. Parallel conductivity was deter- µ of 200 mg/kg s-ketamine (Pfizer, Berlin, Germany), a three- mined by three intravenous injections of 100 L 10% saline. lead electrocardiogram was installed, and the first echocar- Pressure volume loops were recorded during apnea and grad- diographic examination with a 10-MHz probe (Vivid I, GE, ual, short-term reduction of preload. To this end, the infe- Solingen Germany) was performed. The animals were orally rior caval vein was compressed with a cotton bud through a intubated and ventilated with 30% oxygen and 70% nitro- small subxiphoidal incision. After hemodynamic measure- gen in a pressure-controlled mode with a positive end-expi- ments and blood withdrawal, the animals were killed by intravenous injection of potassium chloride and the heart ratory pressure of 5 cm H2O using a closed-circuit anesthesia machine to control the end-tidal carbon dioxide concentra- was excised for further analysis. tion (Physioflex®, Draeger, Luebeck, Germany). The left jug- ular vein was catheterized with a 22G cannula (Leader Flex, Hemodynamic Calculations Vygon, Aachen, Germany) for fluid replacement (10 ml ∙ All signals were collected at a sampling rate of 1000 Hz using kg−1 ∙ h−1 Ringer’s solution) and blood withdrawal. The anes- a data acquisition system (Power Lab 8/30, ADInstruments, thetic depth was evaluated every 30 min by tail pinch. In case Colorado Springs, CO). Time intervals of 10 s were analyzed of limb movement or an increase in heart rate (HR), 50 mg/ with dedicated software (LabChart 6 Pro, ADInstruments kg s-ketamine was injected intraperitoneally. Blood pressure GmbH, Spechbach, Germany; Circlab 2010, Paul Steendijk, was monitored by a 1.4F pressure catheter (SPR-671, Millar Leiden, The Netherlands) at the following time points (see Instruments, Houston, TX) through the right femoral artery. fig.1): At baseline (T0), 50 min after application of inhalative The animals were placed on a feedback-controlled heating narcotics just before start of ischemia (T1), 50 min after pad to maintain the body temperature at 37°C (TCAT-2 induction